Lessons from the past and charting the future of marine natural products drug discovery and chemical biology

Abstract

Marine life forms are an important source of structurally diverse and biologically active secondary metabolites, several of which have inspired the development of new classes of therapeutic agents. These success stories have had to overcome difficulties inherent to natural products-derived drugs, such as adequate sourcing of the agent and issues related to structural complexity. Nevertheless, several marine-derived agents are now approved, most as "first-in-class" drugs, with five of seven appearing in the past few years. Additionally, there is a rich pipeline of clinical and preclinical marine compounds to suggest their continued application in human medicine. Understanding of how these agents are biosynthetically assembled has accelerated in recent years, especially through interdisciplinary approaches, and innovative manipulations and re-engineering of some of these gene clusters are yielding novel agents of enhanced pharmaceutical properties compared with the natural product.

Figure 1

A) Pie chart illustrating the original collected sources of marine natural product derived or inspired agents currently as approved drugs or in clinical trials (20 total). B) Pie chart of the marine-derived drugs and clinical trial agents divided by their subsequently shown or predicted source organisms (20 total).

Figure 2

Pie chart illustrating the collected sources of marine natural products that are available commercially for their useful pharmacological properties in biomedical research (121 total).

Figure 3

Chemical structures of the approved drugs deriving from or inspired by a marine natural product and other marine metabolites discussed in the text (one letter amino acid codes are used for depicting the structure of ziconotide).

Figure 4

Examples of marine natural products from (A) laboratory cultured and (B) environmental uncultured marine microbes whose biosynthetic pathways have been established by a variety of omic approaches (includes ecteinascidin-743 shown in Figure 3).

Figure 5

Assembly line biosynthesis of salinosporamide and library development of structure analogs via mutasynthesis and other genetic engineering approaches.

Figure 6

Parallel strategy employed by Grindberg et al. (2011) to rapidly access the biosynthetic gene cluster for apratoxin A, a promising anticancer lead compound from the marine cyanobacterium Moorea bouillonii. On the top arm, single cells are obtained by microdissection from non-axenic cultures of cyanobacteria, and DNA is extracted and amplified by Multiple Displacement Amplification (MDA) for partial genome sequencing. The sequences of recognizable gene motifs associated with natural product pathways are then used to construct PCR probes to screen a fosmid library which is produced in the normal fashion (lower arm). Fosmids probing positively by this process can be further characterized for desired gene motifs, and then sequenced. The melding of these approaches can accelerate the process of biosynthetic gene cluster discovery and description, such as is illustrated here for apratoxin A, especially in cases of non-axenic cultures or environmental samples.